PROJECT SUMMARY/ABSTRACT Optic neuropathies cause damage to the optic nerve and are leading causes of visual field disturbance and vision loss in adults. Large molecule therapeutics including recombinant antibodies (`biologics') have the potential to revolutionize treatment of these diseases if challenges in delivering them to therapeutic targets within the optic nerve can be overcome. Biologics have had considerable success in treating diseases of the retina, however, intravitreally injected reagents do not enter the optic nerve in significant amounts and delivery of therapeutics to sites of inflammation in optic neuritis therefore requires the development of alternative strategies. Extracellular fluid in brain consists of the cerebrospinal fluid (CSF) found in the ventricles and subarachnoid space and the interstitial fluid (ISF) found in the spaces between nerve cells. Although these compartments are mostly separate, some exchange of solutes can occur via the paravascular spaces, suggesting a potential route for delivery of large molecules to the interstitium, including the optic nerve. Here we will assess the extent to which CSF solutes can accumulate in the optic nerve and test the feasibility of delivering large molecule therapeutics to the optic nerve by intrathecal injection. Experiments in aim 1 will focus on understanding the physiology of extracellular solute transport in the optic nerve. We will inject dextran tracers of various size into the cisterna magna or directly into the optic nerve and follow their transport within the optic nerve. Additional experiments will determine the effect of elevated intraocular pressure on solute transport toward the optic nerve head and determine if deletion of the glial water channel AQP4 alters extracellular solute transport in the optic nerve. Experiments in aim 2 will investigate how the pathways studied in aim1 affect delivery of large molecule therapeutics to the optic nerve; we will investigate the permeability of the optic nerve to antibodies and test delivery of an experimental therapeutic, aquaporumab, to the optic nerve. It is expected that the completion of these experiments will generate compelling evidence for novel drug administration routes in optic neuritis.